1. Field of the Invention
The present invention relates to melatonin formulations which are suitable for parenteral administration. In particular, the present invention relates to formulations comprising melatonin for use for the treatment of neonatal brain injury. The present invention also relates to methods for preventing and/or treating neonatal brain injury.
2. Discussion of the Background
Neonates, especially if born prematurely, are very susceptible to free radical oxidative damage. In fact infants at birth are: a) naturally exposed to hyperoxic challenge due to the transition from the hypoxic intrauterine environment to extrauterine life, and this gap is even more significant for neonates that require supplemental oxygen during resuscitation in the delivery room; b) more susceptible to infection, especially if born prematurely; c) have reduced antioxidant defences; and d) possess high levels of free iron that enhances the Fenton reaction causing the production of highly toxic radicals. Oxidative stress likely contributes also to the severity of several neonates diseases as it may affect a variety of organs, often simultaneously, giving rise to different signs according to the organ most damaged. Said diseases include bronchopulmonary dysplasia/chronic lung disease (BDP/CLD), retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC). Subsequently, it became clear that free radicals are involved in perinatal brain injury as well as in influencing the ductus arteriosus and pulmonary circulation.
In order to counteract free radicals damage many strategies to increase the antioxidant capabilities in term and preterm infants have been proposed and several medications have been experimented with contrasting results.
N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide, known as melatonin, is an endogenous substance mainly synthesized in the pineal gland from the neurotransmitter serotonin. Melatonin plays a key role in a variety of important physiological functions, including regulation of circadian rhythms, as well as visual, reproductive, cerebrovascular, neuroendocrine, and neuro-immunological actions. Melatonin is a highly effective free-radical scavenger which also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes and by augmenting glutathione levels. Melatonin is also known to counteract cellular energy depletion by preserving mitochondrial homeostasis and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. Moreover, melatonin has been shown to attenuate microglial activation and neuroinflammatory responses which are typically associated with hypoxic-ischemic insults. Beside its well documented neuroprotective efficacy, melatonin is an interesting drug, because of its safety profile and its ability to cross all physiological barriers and to reach subcellular compartments.
In light of these properties, during the last decade, melatonin has started to be considered an attractive neuroprotective agent in perinatal asphyxia.
On the other hand, the oral bioavailability of melatonin is low and very variable. Furthermore, melatonin is poorly soluble in water and degrades quickly in water. In the prior art, evidence was reported indicating that melatonin in aqueous solution gradually loses potency at all pH values and is not stable when exposed to light or oxygen. In this respect, it is also well known that some stabilizers and/or preservatives may have the potential to cause toxicological problems, especially in the infant population.
Additionally, the pharmacokinetic profile of melatonin in infants differs from that of adults; therefore dosage of melatonin for term or preterm infants cannot be extrapolated from adult studies. Recently, Robertson N et al (Brain 136(1), 2013, 90-105, which is incorporated herein by reference in its entirety) have shown that melatonin administered intravenously to newborn piglets increases hypothermic neuroprotection at significantly high doses (5 mg/kg/h). Nevertheless, the formulation utilized in this study is not suitable for administration in human neonates.
In view of this background, it would be highly advantageous to provide a physically and chemically stable, safe formulation suitable for parenteral route for the delivery of high dose of melatonin to neonates for the efficacious treatment of a neonatal disease, preferably neonatal brain injury.